Clinical and laboratory evidence continues to demonstrate that androgens and the androgen receptor (AR) are the best available targets for treating/preventing both early and advanced prostate cancer. Numerous clinical trials have been designed to interfere with the AR pathway, but few have actually assessed the effectiveness of the therapy by demonstrating maximal target interference. This proposal aims to use a neoadjuvant clinical trial format to rigorously evaluate the effectiveness of maximal androgen suppression through measurements of intraprostatic androgen levels, and to target a maximal suppression of DHT levels to zero. The clinical benefit of this approach will be evaluated through measurements of tumor grade, stage, margin, tumor cell apoptosis and androgen-regulated gene expression. The aims are: Aim 1. To determine the anti-tumor efficacy of achieving specific (low) intraprostatic androgen levels and inhibition of AR-signaling through direct assessments of tumor viability, apoptosis, proliferation, and androgen-regulated gene expression. Aim 2. To evaluate and compare alternative mechanisms capable of maintaining androgen-activity in a 'castrate' environment in both primary and metastatic prostate cancer: (i) utilization of adrenal androgens; (ii) active androgen transport; (iii) cfenovo biosynthesis of androgens by neoplastic prostate epithelium. Aim 3. To evaluate the pre-clinical efficacy and mechanism(s) of activity of new targeted therapies designed to inhibit testicular, adrenal, and prostatic androgen metabolism and/or AR signaling. The completion of this research project will: 1) demonstrate the efficacy (or lack thereof) of efforts to ablate tissue androgens; 2) measure tumor responses to specific androgen levels and AR inhibition; and 3) provide a context for additional approaches designed to target the AR.